The present invention relates generally to new classes of anti-androgen compounds, their method of synthesis and their use as anti-androgens.
Androgens are one of the five major classes of steroid hormones. Steroid hormones form complexes with receptor proteins which are distributed in a tissue specific fashion within target cells. Jensen, et al., Proc. Nat'l. Acad. Sci. (U.S.A.), 59:632 (1968); Gorski, et al., Ann. Rev. Physiol., 42:17 (1976); and Liao, et al., page 633 in Biochemistry of Hormones, H. L. J. Makin, ed. (Blackwell Sci. Publ. Oxford, 1984). Investigation of he specificity and affinity of steroid hormones for their particular cellular receptors(s) has contributed greatly to the understanding of the relationship between structure and biological activity, target organ specificity, overlaps in hormonal activity, and the mechanism of action of many anti-hormones. Liao, S., et al., J. Biol. Chem., 248:6154 (1973); Liao, S., Biochemical Actions of Hormones (Litwack, G., ed), 4:351, Academic Press, New York (1977); Liao, et al., Biochemistry of Steroid Hormones, (Makin, H. L. J., ed.) pp. 630-680, Blackwell Scientific Publications, Oxford (1984).
Studies on the structural recognition of ligands by steroid receptors suggests that compounds with geometric structures similar to that of natural androgens, such as 5.alpha.-dihydrotestosterone, can bind tightly to androgen receptors and can act either as potent androgens or as anti-androgens. Liao, S., et al., J. Biol. Chem., 248:6154 (1973). The most well known steroidal anti-androgens are cyproterone and its acetate [(Neumann, Androgens and Anti-androgens, (L. Martini and M. Motta, ed.) pp. 163, Raven Press, New York (1977)] which act by interacting with androgen receptors and prevent androgens from binding to the receptors. Fang, S., Molec. Pharmacol., 5:428 (1969). Non-steroidal anti-androgens, such as flutamide-related compounds, also act through the same mechanism. Liao, S., et al., Endocrinol., 94:1205 (1974) and Neri, R., Androgens and Anti-androgens, (L. Martini & M. Motta, ed.) pp. 179, Raven Press, New York (1977).
Studies of the topographic recognition of cyclic hydrocarbons and related compounds by receptors for various steroid hormones have suggested that while the hormonal action of asteroid may be dependent upon the interaction of a functional group present on the hormone with a specific group present on the receptor, the presence of such a functional group may not be required for the antagonistic activities of a compound that can physically block hormone binding to the receptor. Thus, many small molecules, that were hitherto considered to be biologically inert, may interact with steroid receptors specifically and affect hormonal activities in vivo. Chang, C., et al., J. Steroid Biochem., 27:123 (1987). One such example is 9,10-dihydrophenanthrene (DHP) which, in comparison to a natural androgen, lacks one of the rings as well as two functional groups, including a double-bonded oxygen and a hydroxyl group. Despite these differences, DHP nevertheless interacts with androgen receptors in cell-free systems and inhibits the growth of the ventral prostate in rats. Chang, C., et al., J. Steroid Biochem., 27:123 (1987).
Currently, potent anti-androgenic compounds, such as cyproterone and its acetate, and flutamide, are not used in the United States of America because of their side effects, including undesired hormonal activities and/or toxicities.
Thus, there continues to exist a need in the art for new classes of anti-androgens which do not have other hormonal activities and/or side effects, yet, which are useful in treating diseases or abnormalities related to androgen responsive organs.